rs61749721
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001110792.2(MECP2):c.799C>T(p.Arg267*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001110792.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MECP2 | NM_001110792.2 | c.799C>T | p.Arg267* | stop_gained | Exon 3 of 3 | ENST00000453960.7 | NP_001104262.1 | |
| MECP2 | NM_004992.4 | c.763C>T | p.Arg255* | stop_gained | Exon 4 of 4 | ENST00000303391.11 | NP_004983.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MECP2 | ENST00000453960.7 | c.799C>T | p.Arg267* | stop_gained | Exon 3 of 3 | 1 | NM_001110792.2 | ENSP00000395535.2 | ||
| MECP2 | ENST00000303391.11 | c.763C>T | p.Arg255* | stop_gained | Exon 4 of 4 | 1 | NM_004992.4 | ENSP00000301948.6 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 35
GnomAD4 genome
ClinVar
Submissions by phenotype
Rett syndrome Pathogenic:23Other:1
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The observed stop gained c.799C>T p.Arg267Ter variant in MECP2 gene has been previously reported in heterozygous state in multiple individuals affected with classic or atypical Rett syndrome Knight et al., 2013; Deciphering Developmental Disorders Study, 2017; Hettiarachchi et al., 2020. Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression Yusufzai and Wolffe, 2000; Delépine et al., 2013. In addition, a mouse model containing this variant recapitulates a Rett syndrome-like phenotype Pitcher et al., 2015. This variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic multiple submission. Computational evidence MutationTaster - Disease causing predicts damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg267Ter in MECP2 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal p.Arg267Ter in the MECP2 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in MECP2 gene have been previously reported to be disease causing Philippe et al., 2006. For these reasons, this variant has been classified as Pathogenic. -
PVS1,PS2,PM2 -
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This nonsense variant is predicted to cause a truncated protein, which is commonly known mechanism for disease. Variant is absent from large and broad cohorts of the ExAC project while it has been reported in at least ten RTT patients. Many clinical labs and databases classify this variant as pathogenic. Functional studies showed that variant led to deficient transcriptional repression, decreased binding to methylated DNA, and impaired microtubule stability in astrocytes. Considering all, this variant has been classified as pathogenic. -
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Developmental arrest; Repeated hand to mouth movements; Microcephaly; Seizures; Normal development to 6 months of age -
This variant is also referred to in the literature as c.763C>T (p.Arg255Ter) due to use of a different reference transcript (NM_004992.3). This nonsense variant found in exon 3 of 3 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple unrelated individuals with classic or atypical Rett syndrome (PMID: 23270700, 28135719, 17089071, 10508514, 31535341). Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression (PMID: 23238081, 11058114). In addition, a mouse model containing this variant recapitulates a Rett syndrome-like phenotype (PMID: 25634563). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.799C>T (p.Arg267Ter) variant is classified as Pathogenic. -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Rett syndrome (MIM#312750). (I) 0108 - This gene is associated with both recessive and dominant disease. Rett syndrome is inherited in an X-linked dominant pattern, while MECP2-related encephalopathy and intellectual disability display X-linked recessive inheritance (PMID: 20301670). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in many individuals with Rett syndrome by clinical laboratories in ClinVar. (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4)(PP4). Is a common, recurrent pathogenic variant ,identified as a de novo occurrence in at least one individual with Rett syndrome (PM6).(PMID: 20301670 , ClinVar database Variation ID: 11829) -
This variant was previously reported in multiple unrelated individuals with Rett syndrome [PMID: 23270700, 21982064, 23810759,10508514, 17089071] including several de novo observations. This variant was classified a pathogenic [PMID: 23810759] and reported to be associated with bone disease severity in subjects with Rett syndrome [ PMID: 32005172]. In-vitro functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and transcriptional repression [PMID: 23238081, 11058114]. In addition, mouse models harboring this variant recapitulates Rett syndrome-like phenotypes [PMID: 25634563, 32927061]. -
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24526180). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.85 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.52 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000046131 /PMID: 17551081 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23958653, 24526180). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 23958653). A different missense change at the same codon (p.Ala306Val) has been reported to be associated with TMPRSS3 related disorder (ClinVar ID: VCV002445668). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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not provided Pathogenic:13
The MECP2 c.763C>T, p.Arg255Ter variant (rs61749721) induces an early termination codon and is predicted to result in a truncated protein or absent transcript. This variant is one of the most common disease causing variants of Rett syndrome (RTT) (Neul 2008), and has been associated with both classical and atypical RTT (see link to RettBASE and references therein). Functional studies showed p.Arg255Ter to be less stable in vivo and lead to deficient transcriptional repression (Yusufzai 2000). Furthermore, this variant is reported as pathogenic in ClinVar (Variation ID: 11829), and is absent from population databases (Exome Variant Server, Exome Aggregation Consortium). Therefore, this variant is considered to be pathogenic. REFERENCES Link to RettBASE: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Neul JL et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008; 70(16):1313-21. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9. -
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PM2, PM6, PS4, PVS1_strong -
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The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -
Published many times in association with both classic and atypical Rett syndrome (for examples, see Hoffbuhr et al., 2001; Yamada et al., 2001; Neul et al., 2008; Lima et al., 2009); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Functional studies indicate this variant affects the protein's ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31512412, 31535341, 31139143, 30829465, 31134136, 30536762, 29655203, 30564305, 28135719, 28399682, 28263302, 26175308, 16077729, 27824329, 19722030, 18337588, 11524741, 11402105, 23238081, 10508514, 11058114, 25634563, 21575601, 23270700, 18174548) -
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MECP2-related disorder Pathogenic:3
The variant NM_004992.4:c.763C>T (p.Arg267)* introduces a premature stop codon at codon 267, which is predicted to result in a truncated protein or nonsense-mediated decay (NMD). According to ACMG/AMP guidelines, this variant meets the criteria for PS3, PVS1, PM2, and PP5, supporting its classification as pathogenic -
This variant is also referred to in the literature as c.763C>T (p.Arg255Ter) due to use of a different reference transcript (NM_004992.3). This nonsense variant found in exon 3 of 3 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple unrelated individuals with classic or atypical Rett syndrome (PMID: 23270700, 28135719, 17089071, 10508514, 31535341). Loss-of-function variation in MECP2 is an established mechanism of disease (PMID: 22781840, 26942018, 31527487). Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression (PMID: 23238081, 11058114). In addition, a mouse model containing this variant recapitulates a Rett syndrome-like phenotype (PMID: 25634563). The c.799C>T (p.Arg267Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.799C>T (p.Arg267Ter) variant is classified as Pathogenic. -
The MECP2 c.763C>T variant is predicted to result in premature protein termination (p.Arg255*). This variant has previously been reported to be causative for Rett Syndrome (Amir et al. 1999. PubMed ID: 10508514; Yusufzai et al. 2000. PubMed ID: 11058114; Pitcher et al. 2015. PubMed ID: 25634563) and it occurred de novo (Wang et al. 2019. PubMed ID: 31512412). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in MECP2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Pathogenic:2
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MECP2 NM_004992.3 exon 4 p.Arg255* (c.763C>T): This variant has been reported in the literature in numerous (n>100) individuals with Rett syndrome (select publications: Amir 1999 PMID:10508514, Knight 2013 PMID:23270700, McRae 2017 PMID:28135719, Hettiarachchi 2019 PMID:31535341, RettBASE). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:11829). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In addition, functional studies have shown a deleterious effect of this variant (Yusufzai 2000 PMID:11058114, Delepine 2013 PMID:23238081, Pitcher 2015 PMID:25634563). However, these studies may not accurately represent in vivo biological function. The vast majority of pathogenic variants are identified in exon 4 which encodes for the methyl binding domain and transcription repression domain. This variant creates a premature stop at this codon within exon 4 which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Philippe 2006 16473305). In summary, this variant is classified as pathogenic based on the data above. -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg255*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 232 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 1241840, 10508514, 17089071, 23270700). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11829). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID: 11058114, 23238081, 25634563). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Arg270*) have been determined to be pathogenic (PMID: 11058114, 11241840, 18174548, 23238081). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Neurodevelopmental delay Pathogenic:1
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Syndromic X-linked intellectual disability Lubs type Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.763C>T (p.R255*) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, results from a C to T substitution at nucleotide position 763. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 255. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts nearly half of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been detected in multiple individuals who meet classical clinical criteria for Rett syndrome and is a commonly reported nonsense mutation in the literature (Amir, 1999; Laccone, 2001; Li, 2007; Delépine, 2013). Based on the available evidence, this alteration is classified as pathogenic. -
Abnormality of the nervous system Pathogenic:1
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X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
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Autism Pathogenic:1
Known mutation in known disease gene -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at